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NRTIs’ effect on the sequence of mitochondrial
DNA HV 2 in HIV infected patients |
Ya-Song WU MD, PhD1,Xin-Yue CHEN MD2,Ying SHI PhD2,Hao WU MD2,De-Xi CHEN MD, PhD2,Yu SUN MD2,Fu-Jie ZHANG MD3, |
1.Division of Treatment
and Care, National Center for AIDS/STD Control and Prevention, Chinese
Center for Disease Control and Prevention, Beijing 102206, China; 2.Center for Infectious
Diseases, Beijing You’an Hospital, Capital Medical University,
Beijing 100069, China; 3.Division of Treatment
and Care, National Center for AIDS/STD Control and Prevention, Chinese
Center for Disease Control and Prevention, Beijing 102206, China;Beijing Ditan Hospital,
Beijing 100015, China; |
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Abstract Potent combination antiretroviral therapy (cART) has significantly improved the life expectancy of people living with human immunodeficiency virus (HIV), but it has many side effects such as lipodystrophy (LD), hepatic steatosis, and lactic acidosis. Nucleoside reverse transcriptase inhibitors (NRTIs) could damage the mitochondria by inhibiting the human DNA polymerase gamma, leading to mtDNA deletion. However, it remains uncertain whether NRTIs could induce the hypervariable region (HV) mutations of the D loop of mitochondria in Chinese HIV/AIDS patients, and whether that effect is different between individuals with and without LD. Hereby, 30 Chinese AIDS patients who were receiving antiretroviral drugs were recruited, among which 16 had symptomatic LD and 14 did not. Blood samples were collected prior to and after 96 weeks of treatment. Total DNA was extracted from peripheral blood mononuclear cells (PBMCs). Fragments of 728 bp in length containing HV 2 were amplified by standard polymerase chain reaction (PCR). Direct DNA-sequencing analysis techniques were used to detect mitochondrial sequence variants between paired longitudinal samples. Alterations were compared with the revised Cambridge Reference Sequence (rCRS) to determine mutation or polymorphism. Results showed that two years after ART, totally seven cases exhibited sequence variations, five individuals showed 73€A→G revised variation (two with and three without LD), while two cases of LD were found to have other nucleotide alterations. There was no new alteration in individuals without LD. In conclusion, NRTIs could induce mutation of mtDNA HV 2, which might contribute to the development of LD.
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Keywords
nucleoside reverse transcriptase inhibitors
human immunodeficiency virus
mitochondrial DNA
D loop
mutation
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Issue Date: 05 June 2010
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Kohler J J, Lewis W. A brief overviewof mechanisms of mitochondrial toxicity from NRTIs. Environ Mol Mutagen, 2007, 48(3―4): 166―172
doi: 10.1002/em.20223
|
|
Wu Y, Li N, Zhang T, Wu H, Huang C, Chen D. Mitochondrial DNA base excision repair and mitochondrialDNA mutation in human hepatic HuH-7 cells exposed to stavudine. Mutat Res, 2009, 664(1―2): 28―38
doi: 10.1016/j.mrfmmm.2009.02.006
|
|
Andrews R M, Kubacka I, Chinnery P F, Lightowlers R N, Turnbull D M, Howell N. Reanalysis and revision ofthe Cambridge reference sequence for human mitochondrial DNA. Nat Genet, 1999, 23(2): 147
doi: 10.1038/13779
|
|
Anderson S, Bankier A T, Barrell B G, de Bruijn M H, Coulson A R, Drouin J, Eperon I C, Nierlich D P, Roe B A, Sanger F, Schreier P H, Smith A J, Staden R, Young I G. Sequenceand organization of the human mitochondrial genome. Nature, 1981, 290(5806): 457―465
doi: 10.1038/290457a0
|
|
Barthelemy C, de Baulny H O, Lombes A. D-loop mutations in mitochondrialDNA: link with mitochondrial DNA depletion? Hum Genet, 2002, 110(5): 479―487
doi: 10.1007/s00439-002-0708-4
|
|
Martin A M, Hammond E, Nolan D, Pace C, Den Boer M, Taylor L, Moore H, Martinez O P, Christiansen F T, Mallal S. Accumulation of mitochondrial DNA mutations in humanimmunodeficiency virus-infected patients treated with nucleoside-analoguereverse-transcriptase inhibitors. Am JHum Genet, 2003, 72(3): 549―560
doi: 10.1086/367849
|
|
McComsey G, Tan D J, Lederman M, Wilson E, Wong L J. Analysis of the mitochondrialDNA genome in the peripheral blood leukocytes of HIV-infected patientswith or without lipoatrophy. AIDS, 2002, 16(4): 513―518
doi: 10.1097/00002030-200203080-00001
|
|
Weinberg J B, Muscato J J, Niedel J E. Monocyte chemotactic peptidereceptor. Functional characteristics and ligand-induced regulation. J Clin Invest, 1981, 68(3): 621―630
doi: 10.1172/JCI110296
|
|
Timmermans E C, Tebas P, Ruiter J P, Wanders R J, de Ronde A, de Baar M P. Real-time nucleic acid sequence-based amplification assayto quantify changes in mitochondrial DNA concentrations in cell culturesand blood cells from HIV-infected patients receiving antiviral therapy. Clin Chem, 2006, 52(6): 979―987
doi: 10.1373/clinchem.2005.062901
|
|
www.mitomap.org/MITOMAP/HumanMitoSeq
|
|
Crum-Cianflone N, Hullsiek K H, Marconi V, Weintrob A, Ganesan A, Barthel R V, Fraser S, Agan B K, Wegner S. Trends in the incidence of cancers amongHIV-infected persons and the impact of antiretroviral therapy: a 20-yearcohort study. AIDS, 2009, 23(1): 41―50
doi: 10.1097/QAD.0b013e328317cc2d
|
|
Mercier S, Gueye N F, Cournil A, Fontbonne A, Copin N, Ndiaye I, Dupuy A M, Cames C, Sow P S, Ndoye I, Delaporte E, Simondon K B. Lipodystrophy and metabolic disorders in HIV-1-infected adults on4- to 9-year antiretroviral therapy in Senegal: a case-control study. J Acquir Immune Defic Syndr, 2009, 51(2): 224―230
doi: 10.1097/QAI.0b013e31819c16f4
|
|
Brinkman K, Smeitink J A, Romijn J A, Reiss P. Mitochondrial toxicity induced by nucleoside-analoguereverse-transcriptase inhibitors is a key factor in the pathogenesisof antiretroviral-therapy-related lipodystrophy. Lancet, 1999, 354(9184): 1112―1115
doi: 10.1016/S0140-6736(99)06102-4
|
|
Kakuda T N, Brundage R C, Anderson P L, Fletcher C V. Nucleoside reverse transcriptase inhibitor-induced mitochondrialtoxicity as an etiology for lipodystrophy. AIDS, 1999, 13(16): 2311―2312
doi: 10.1097/00002030-199911120-00019
|
|
Shikuma C M, Hu N, Milne C, Yost F, Waslien C, Shimizu S, Shiramizu B. MitochondrialDNA decrease in subcutaneous adipose tissue of HIV-infected individualswith peripheral lipoatrophy. AIDS, 2001, 15(14): 1801―1809
doi: 10.1097/00002030-200109280-00009
|
|
McComsey G A, Paulsen D M, Lonergan J T, Hessenthaler S M, Hoppel C L, Williams V C, Fisher R L, Cherry C L, White-Owen C, Thompson K A, Ross S T, Hernandez J E, Ross L L. Improvements in lipoatrophy, mitochondrial DNA levelsand fat apoptosis after replacing stavudine with abacavir or zidovudine. AIDS, 2005, 19(1): 15―23
doi: 10.1097/00002030-200501030-00002
|
|
Nolan D, Hammond E, Martin A, Taylor L, Herrmann S, McKinnon E, Metcalf C, Latham B, Mallal S. Mitochondrial DNA depletionand morphologic changes in adipocytes associated with nucleoside reversetranscriptase inhibitor therapy. AIDS, 2003, 17(9): 1329―1338
doi: 10.1097/00002030-200306130-00007
|
|
McComsey G, Bai R K, Maa J F, Seekins D, Wong L J. Extensive investigationsof mitochondrial DNA genome in treated HIV-infected subjects: beyondmitochondrial DNA depletion. J Acquir ImmuneDefic Syndr, 2005, 39(2): 181―188
|
|
Williams R S. Mitochondrial gene expression in mammalian striated muscle.Evidence that variation in gene dosage is the major regulatory event. J Biol Chem, 1986, 261(26): 12390―12394
|
|
Veltri K L, Espiritu M, Singh G. Distinct genomic copy numberin mitochondria of different mammalian organs. J Cell Physiol, 1990, 143(1): 160―164
doi: 10.1002/jcp.1041430122
|
|
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